It is well established that genetic factors play a major role in breast tumorigenesis. However, the known breast cancer susceptibility genes account for only a minority of breast cancer cases in the general population. Cumulative evidence from in vitro and animal studies suggests that the genes involved in the cell-cycle control and apoptosis pathways may be related to breast cancer. The cell-cycle control and apoptosis pathways function as an integrated molecular network, and perturbations in one pathway can have profound consequences on the other. In this application, we propose to investigate genetic variations of major genes involved in the cell- cycle control and apoptosis pathways in relation to breast cancer risk. The proposed study will use data and biological samples collected from the Shanghai Breast Cancer Study (SBCS, R01CA64277). Genetic polymorphisms in 25 candidate genes in the cell-cycle control and apoptosis pathways will initially be evaluated using both the genotype- and haplotype- approaches in 1,250 cases and 1,250 controls recruited from 1996 to 1998. Promising associations identified in the initial phase will be re-evaluated in a second set of subjects (1,850 cases and 1,850 controls) recruited from 2002 to 2005. This two-phase study design will effectively balance both Type I and Type 2 statistical errors and provide credible results towards our understanding of the etiology of breast cancer. We will use the multifactor-dimensionality reduction (MDR) statistical method to investigate any gene-gene interaction in relation to breast cancer risk. We will investigate interaction between genetic polymorphisms with endogenous estrogen exposure related factors in relation to breast cancer risk. We will evaluate whether genetic polymorphisms may be associated with the risk of specific subtypes of breast cancer. We will also conduct in vitro experiments to evaluate the function of genetic variations to further confirm the biological relevance of the association. With its large size and strong methodology, the SBCS provides a great opportunity to investigate gene-gene and gene-environment interactions in relation to breast cancer risk. The findings from the proposed study are likely to significantly advance our knowledge of the etiology of breast cancer and will be valuable for identifying high risk women for the primary and secondary prevention of breast cancer. We propose to investigate genetic variations of major genes involved in the cell-cycle control and apoptosis pathways in relation to breast cancer risk. The findings from the proposed study are likely to significantly advance our knowledge of the etiology of breast cancer and will be valuable for identifying high risk women for the primary and secondary prevention of breast cancer.